Cyclic guanosine monophosphate (cGMP), which is implicated in cardiac cell growth and function, is synthesized by cytoplasmic soluble guanylyl cyclase (GC) stimulated via nitric oxide (NO) and by particulate membrane-bound GC activated via natriuretic peptides. We investigated possible cGMP elevation in the left ventricle (LV) of rats developing physiologic LV hypertrophy during gestation. Furthermore, expression of estrogen receptors (ER) and oxytocin receptors (OTR) was evaluated because their activation stimulates NO and atrial natriuretic peptide (ANP) release from the heart. Compared with nonpregnant controls, Sprague-Dawley rats on day 7 of gestation had similar heart weights, but, on days 14 and 21, ventricular mass increased by 12% and 28% respectively (P< 0.05). LV cGMP concentration was elevated at day 14 of gestation (3.25 ± 0.12 vs 4.65 ± 0.17 pmol/g wet weight, P< 0.01) but decreased at day 21 (2.45 ± 0.09 pmol/g, P< 0.05) to increase again on postpartum day 1 (6.01 ± 0.15 pmol/g) and day 4 (9.21 ± 1.79 pmol/g). Changes in endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), OTR and ERα, but not ERβ, proteins paralleled the pregnancy-related cGMP changes in the LV. In contrast, ANP mRNA of the LV remained at control level throughout gestation but increased postpartum, whereas brain natriuretic peptide (BNP) expression declined at term and increased postpartum. The particulate GC natriuretic peptide receptors (GC-A and GC-B) transcripts were already lower at day 14 of gestation. Natriuretic peptide clearance receptor (NPR-C) transcript was not altered on days 7 and 14, but increased at term. We conclude that cGMP concentration in the rat LV is influenced by both NOS and natriuretic peptide systems and may be involved in the changes of LV contractility and hypertrophy that occur during rat gestation.
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M Jankowski, D Wang, S Mukaddam-Daher, and J Gutkowska
S Mukaddam-Daher, M Jankowski, D Wang, A Menaouar, and J Gutkowska
We have recently uncovered the presence of an oxytocin system in the heart and found that oxytocin is a physiological regulator of atrial natriuretic peptide (ANP), a diuretic, natriuretic and vasodilator cardiac hormone. However, dynamic changes in these systems during gestation, when mechanisms of volume and pressure homeostasis are altered, are not clear. Accordingly, ANP, oxytocin and oxytocin receptors were evaluated in rat hearts and plasma at three stages of gestation (7, 14 and 21 days) and at 2 and 5 days postpartum. Compared with non-pregnant controls, plasma ANP was elevated in mid-gestation, but significantly decreased at term (21 days), to increase again postpartum. Right and left atrial ANP mRNA levels were not altered throughout gestation but increased by 1.5- to 2-fold postpartum (P<0.01). At term, ANP content in right (8.7+/-1.2 vs 12.7+/-1.1 micro g/mg protein, P<0.04) and left (3.5+/-0.6 vs 8.5+/-2.0 micro g/mg protein, P<0.01) atria increased. These findings imply that decreased plasma ANP at term results from inhibition of release rather than decreased synthesis. In parallel, oxytocin, a stimulator of ANP release, decreased in left atria at day 7 to 50% of non-pregnant levels and remained low throughout gestation. Oxytocin receptor mRNA increased in left atria at 7 and 14 days of gestation by 2- and 5-fold respectively, but decreased at 21 days to lower than non-pregnant levels to increase again (3-fold) postpartum. The changes in oxytocin receptor expression at term and postpartum paralleled oxytocin receptor protein determined by Western blot. These results imply that pregnancy is associated with dynamic changes in the cardiac oxytocin system (peptide and/or receptors), which may influence natriuretic peptide release. Together, these peptides would act on their receptors in the heart, vasculature and kidneys to maintain vascular tone and renal function throughout gestation and postpartum.
A M Reis, M Jankowski, S Mukaddam-Daher, J Tremblay, T-V Dam, and J Gutkowska
Uterine natriuretic peptides may be involved in the alterations that occur in the uterus during the estrous cycle through its role in hydromineral balance. The following studies were performed to determine whether uterine natriuretic peptides and receptors follow a cyclic pattern during the estrous cycle. The results obtained show that atrial natriuretic peptide (ANP) content in rat uterine tissue was low in proestrus (8·5 ± 2·6 pg/g) and significantly increased (P<0·001) in estrus (71·5 ± 16·6 pg/g), metestrus (82·6 ± 19·7 pg/g) and diestrus (91·0 ± 19·4 pg/g), whereas plasma ANP was not altered during the cycle. Similarly, measurement of uterine ANP mRNA by reverse transcribed polymerase chain reaction (RT-PCR) indicated lowest levels of ANP mRNA at proestrus. Measurement of C-type natriuretic peptide (CNP) by a specific and sensitive radioimmunoassay revealed that uterine CNP also varies with the estrous cycle. Uterine CNP was low in diestrus (143·2 ± 22·4 pg/mg protein) as compared with proestrus, estrus and metestrus (305·3 ± 51·5, 267·5 ± 44·9, 291 ± 41·2 pg/mg protein respectively, P<0·05). Autoradiography performed on uterine tissue slices localized natriuretic peptide receptors to myometrial smooth muscle layers and to endometrial uterine glands. High binding of 125I-ANP was observed in proestrus and estrus with 60–75% decreases during metestrus and diestrus. Binding of 125I-tyr0CNP to uterine slices was also high during proestrus, but declined by 35% at estrus, metestrus and diestrus. The alterations in the receptors were also observed at the level of synthesis. RT-PCR detection of guanylyl cyclase A (GC-A) receptor mRNA and guanylyl cyclase B (GC-B) mRNA showed high signals at proestrus but 4- and 2-fold reductions respectively at metestrus and diestrus. In conclusion, variations in uterine ANP and CNP and their receptors during the rat estrous cycle imply the involvement of the natriuretic peptides in uterine hydromineral balance and myometrial motor activity.
Journal of Endocrinology (1997) 153, 345–355